| RRC ID |
43107
|
| 著者 |
Kajiguchi T, Chung EJ, Lee S, Stine A, Kiyoi H, Naoe T, Levis MJ, Neckers L, Trepel JB.
|
| タイトル |
FLT3 regulates beta-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells.
|
| ジャーナル |
Leukemia
|
| Abstract |
Deregulated accumulation of nuclear beta-catenin enhances transcription of beta-catenin target genes and promotes malignant transformation. Recently, acute myeloid leukemia (AML) cells with activating mutations of FMS-like tyrosine kinase-3 (FLT3) were reported to display elevated beta-catenin-dependent nuclear signaling. Tyrosine phosphorylation of beta-catenin has been shown to promote its nuclear localization. Here, we examined the causal relationship between FLT3 activity and beta-catenin nuclear localization. Compared to cells with wild-type FLT3 (FLT3-WT), cells with the FLT3 internal tandem duplication (FLT3-ITD) and tyrosine kinase domain mutation (FLT3-TKD) had elevated levels of tyrosine-phosphorylated beta-catenin. Although beta-catenin was localized mainly in the cytoplasm in FLT3-WT cells, it was primarily nuclear in FLT3-ITD cells. Treatment with FLT3 kinase inhibitors or FLT3 silencing with RNAi decreased beta-catenin tyrosine phosphorylation and nuclear localization. Conversely, treatment of FLT3-WT cells with FLT3 ligand increased tyrosine phosphorylation and nuclear accumulation of beta-catenin. Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML.
|
| 巻・号 |
21(12)
|
| ページ |
2476-84
|
| 公開日 |
2007-12-1
|
| DOI |
10.1038/sj.leu.2404923
|
| PII |
2404923
|
| PMID |
17851558
|
| MeSH |
Active Transport, Cell Nucleus / physiology*
Acute Disease
Animals
Cell Line, Tumor
Gene Expression Regulation, Leukemic*
Glycogen Synthase Kinase 3 / antagonists & inhibitors
Glycogen Synthase Kinase 3 / physiology
Glycogen Synthase Kinase 3 beta
Humans
Interleukin-3 / pharmacology
Leukemia, Myeloid / genetics
Leukemia, Myeloid / metabolism*
Leukemia, Myeloid / pathology
Membrane Proteins / pharmacology
Mice
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / physiology*
Phosphorylation
Phosphotyrosine / metabolism
Protein Processing, Post-Translational / physiology*
RNA, Small Interfering / pharmacology
Recombinant Proteins / metabolism
Staurosporine / analogs & derivatives
Staurosporine / pharmacology
Transcription, Genetic / physiology*
Tyrphostins / pharmacology
beta Catenin / genetics
beta Catenin / metabolism*
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / physiology*
|
| IF |
8.665
|
| 引用数 |
29
|
|
WOS 分野
|
HEMATOLOGY
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
32D(RCB1145) |
